IL-33 signaling as a target to reduce ventilator-induced lung inflammation

IL-33 信号传导作为减少呼吸机引起的肺部炎症的靶点

• 批准号: 10704302
• 负责人: Guido Musch
• 金额: $ 81.02万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10704302
• 关键词: Acute Respiratory Distress Syndrome; Address; Affinity; Allergic inflammation; Binding; Biological; Biological Markers; Biological Response Modifier Therapy; Blocking Antibodies; Cell membrane; Cells; Clinical; Critical Illness; Data; Epidemic; Epithelial; Gene Expression; General Anesthesia; Genetic Transcription; Goals; Hour; Immune; Inflammation; Inflammation Mediators; Inflammatory; Injury; Intensive Care Units; Interleukin-1 Receptors; Interleukin-13; Interleukin-4; Interleukin-5; Interleukin-6; Interruption; Intubation; Knockout Mice; Knowledge; Lead; Light; Link; Lung; MAP Kinase Gene; Measures; Mechanical ventilation; Mechanics; Mediating; Mediator of activation protein; Methods; Modeling; Morbidity - disease rate; Mus; Operating Rooms; Operative Surgical Procedures; Organ; Pathogenesis; Pathway interactions; Patients; Pilot Projects; Poliomyelitis; Positron-Emission Tomography; Postoperative Period; Process; Production; Proteins; Pulmonary Inflammation; Rattus; Recombinants; Reporter; Reporting; Research; Resolution; Role; Signal Pathway; Signal Transduction; Testing; Th2 Cells; Therapeutic; Therapeutic Intervention; Tidal Volume; Time; Transgenic Organisms; Treatment Efficacy; Ventilator; Ventilator-induced lung injury; clinical practice; clinically relevant; cytokine; effective therapy; experimental study; imaging modality; immunogenicity; improved; in vivo; interest; mechanical pressure; mechanical stimulus; molecular imaging; mortality; mouse model; non-invasive imaging; novel; preventive intervention; public health relevance; receptor; response; stem; therapeutic target; uptake; ventilation

PROJECT SUMMARY/ABSTRACT Since being heralded into clinical practice by the Danish polio epidemic of 1952, positive pressure mechanical ventilation has saved countless lives and enabled the safe practice of surgery under general anesthesia. In recent years, however, it has become clear that mechanical ventilation itself can injure the lung by initiating and propagating an inflammatory process termed ventilator-induced lung injury (VILI). Whereas VILI was initially mainly considered an aggravating factor for critically ill patients with acute respiratory distress syndrome, new evidence suggests that it can occur also in subjects with uninjured lungs undergoing ventilation for other reasons, for example while receiving general anesthesia. The long-term goal of this research is to dissect the mechanisms of VILI and identify strategies to ameliorate it. The proposed studies align with this goal because they investigate a novel role for the IL-33/ST2 signaling pathway by addressing the overarching hypothesis that IL-33 is an upstream pathogenetic effector of VILI through its effect on NF-κB mediated inflammation. This hypothesis will be tested through three closely knit specific aims. Aim 1 will establish the role of IL-33 in VILI by demonstrating that its expression increases with tidal volume, that it parallels the response of established VILI cytokines and NF-κB, and that IL-33 deletion blunts such response. Aim 2 builds on aim 1 by probing the efficacy of IL-33 scavenging with IL-33 decoy receptors as an approach for interrupting IL-33/ST2/NF-κB signaling and decreasing inflammation in VILI. This aim will leverage a novel biologic with high affinity for IL-33 (“IL-33 trap”) that preliminary data suggest could have therapeutic potential. The IL-33 trap will be compared with the more traditional approach of anti-ST2 receptor blocking antibodies. Aim 3 flows from aims 1 and 2 as it will determine for how long the activation of NF-κB triggered by release of mechano- sensitive cytokines like IL-33 persists after ventilation ceases, thus rendering the lung vulnerable to other insults, as are those that can occur in the postoperative period. A distinctive feature that permeates all three aims of this project is the application of a unique molecular imaging method based on positron emission tomography (PET) of NF-κB transcriptional activity to measure the effect of IL-33/ST2 signaling on downstream cytokine expression in vivo, noninvasively, repeatedly and with high spatial resolution. It is expected that the combination of clinically relevant murine ventilation model, novel VILI effector (IL-33, aim 1), therapeutic biologic (IL-33 trap, aim 2), and translational perspective (aim 3), will make the proposed experiments uniquely poised to yield fundamental new knowledge on the pathogenesis of VILI and on potential preventative and therapeutic strategies.

项目摘要/摘要 自从1952年丹麦脊髓灰质炎流行病预示着临床实践以来，正压 通风挽救了无数的生命，并在全身麻醉下实现了手术的安全实践。在 然而，近年来，很明显，机械通气本身可能通过发起来伤害肺部 并传播称为呼吸机诱导的肺损伤（VILI）的炎症过程。而Vili是 最初主要认为患有急性呼吸障碍的重症患者的加重因素 综合征，新的证据表明，它也可以发生在接受通风的受试者中 出于其他原因，例如在接受全身麻醉时。这项研究的长期目标是 解剖维利的机制并确定改善它的策略。拟议的研究与此一致 目标是因为他们通过解决总体来研究IL-33/ST2信号通路的新作用 假设IL-33是VILI通过其对NF-κB介导的影响的上游致病效应。 炎。该假设将通过三个紧密编织的特定目的进行检验。 AIM 1将确定 IL-33在VILI中的作用通过证明其表达随潮汐体积的增加而与 已建立的VILI细胞因子和NF-κB的响应，IL-33删除这种反应。 AIM 2构建 通过探测IL-33用IL-33诱饵受体清除IL-33的效率，作为中断的方法 IL-33/ST2/NF-κB信号传导和VILI注射减少。这个目标将利用一种新颖的生物学 初步数据表明可能具有治疗潜力的IL-33（“ IL-33陷阱”）的高亲和力。 IL-33 将陷阱与抗ST2受体阻断抗体的更传统方法进行比较。目标3流 从目标1和2中，它将决定通过释放机械触发的NF-κB激活多长时间 通风后，诸如IL-33之类的敏感细胞因子持续存在，从而使肺部易受其他影响。 侮辱，术后可能发生的侮辱。一个独特的功能，渗透到这三个 该项目的目的是基于正电子发射的独特分子成像方法的应用 NF-κB转录活性的断层扫描（PET），以测量IL-33/ST2信号对下游的影响 体内的细胞因子表达，无创，反复，空间分辨率高。期望 临床相关的鼠通气模型，新型VILI效应子（IL-33，AIM 1）的组合，治疗 生物学（IL-33陷阱，AIM 2）和翻译的视角（AIM 3）将使提出的实验独特 中毒以产生有关Vili和潜在预防性发病机理的基本知识 治疗策略。